tbuckley/cabot-search huggingface dataset:
Revisiting regulatory T cells for stroke therapy
Authors: Juneyoung Lee, Louise D. McCullough
Journal: Journal of Clinical Investigation (2022)

Stroke is a leading cause of death and long-term disability. T cells have been extensively studied for their dual role in regulating immunity and inflammation following stroke. In this issue of the JCI, Cai, Shi, et al. demonstrated that CD8+ regulatory-like T cells (CD8+ TRLs) are one of the earliest lymphocyte subtypes to enter the brain after experimental ischemic stroke. Using a mouse model of stroke and comprehensive experimental approaches, the authors found that CD8+ TRLs reduced both brain damage and functional deficits in both young and aged mice. These unique early responding regulatory T cells may also play a role in a wide array of other T cell–mediated neurological disorders.
Cellular senescence: a key therapeutic target in aging and diseases
Authors: Lei Zhang, Louise E. Pitcher, Matthew J. Yousefzadeh, Laura J. Niedernhofer, Paul D. Robbins, Yi Zhu
Journal: Journal of Clinical Investigation (2022)

Cellular senescence is a hallmark of aging defined by stable exit from the cell cycle in response to cellular damage and stress. Senescent cells (SnCs) can develop a characteristic pathogenic senescence-associated secretory phenotype (SASP) that drives secondary senescence and disrupts tissue homeostasis, resulting in loss of tissue repair and regeneration. The use of transgenic mouse models in which SnCs can be genetically ablated has established a key role for SnCs in driving aging and age-related disease. Importantly, senotherapeutics have been developed to pharmacologically eliminate SnCs, termed senolytics, or suppress the SASP and other markers of senescence, termed senomorphics. Based on extensive preclinical studies as well as small clinical trials demonstrating the benefits of senotherapeutics, multiple clinical trials are under way. This Review discusses the role of SnCs in aging and age-related diseases, strategies to target SnCs, approaches to discover and develop senotherapeutics, and preclinical and clinical advances of senolytics.
Long COVID endotheliopathy: hypothesized mechanisms and potential therapeutic approaches
Authors: Jasimuddin Ahamed, Jeffrey Laurence
Journal: Journal of Clinical Investigation (2022)

SARS-CoV-2–infected individuals may suffer a multi–organ system disorder known as "long COVID" or post-acute sequelae of SARS-CoV-2 infection (PASC). There are no standard treatments, the pathophysiology is unknown, and incidence varies by clinical phenotype. Acute COVID-19 correlates with biomarkers of systemic inflammation, hypercoagulability, and comorbidities that are less prominent in PASC. Macrovessel thrombosis, a hallmark of acute COVID-19, is less frequent in PASC. Female sex at birth is associated with reduced risk for acute COVID-19 progression, but with increased risk of PASC. Persistent microvascular endotheliopathy associated with cryptic SARS-CoV-2 tissue reservoirs has been implicated in PASC pathology. Autoantibodies, localized inflammation, and reactivation of latent pathogens may also be involved, potentially leading to microvascular thrombosis, as documented in multiple PASC tissues. Diagnostic assays illuminating possible therapeutic targets are discussed.
Concerns about the inverse relationship between baseline HBV DNA and on-treatment hepatocellular carcinoma risk
Authors: Shi Liu, Yongyin Li, Jian Sun
Journal: Journal of Clinical Investigation (2022)

We read with great interest the article by Choi et al., which concluded that baseline HBV DNA level was inversely associated with on-treatment hepatocellular carcinoma (HCC) risk in HBeAg-positive, noncirrhotic, chronic hepatitis B (CHB) patients (1).Their findings are novel, but several issues deserve discussion.Firstly, the representativeness and potential selection bias for the study subjects are crucial, which will significantly influence the robustness and generalizability of study results.It's uncertain whether the study subjects were enrolled consecutively, since only 2457 patients were included during the nearly ten-year enrollment at three centers.Independent cohorts with large sample size are needed to validate the conclusion.Secondly, many confounders, like obesity, diabetes, drinking, and treatment response, were not adjusted in this study.Although the results were reproduced after excluding patients who did not achieve HBV DNA of less than 2000 IU/mL at year one, the effect of longitudinal virological response on HCC risk couldn't be ignored.Besides, biochemical response, which has been shown to be associated with HCC risk (2), was also not adjusted.Thirdly, it is widely accepted that high levels of HBV DNA were associated with increased HCC risk in the natural history cohort (3).However, this study showed opposite results in the nucleos(t) ide analogue-treated (NA-treated) cohort.We understand that HBeAg-positive patients in the immune-active phase, which are the target population of this study, are characterized by fluctuating but progressively decreasing HBV DNA levels, elevated alanine aminotransferase (ALT), and accumulated hepatic necroinflammation and fibrosis (4).It's reasonable to speculate that lower baseline HBV DNA may indicate more advanced liver disease, which is a key risk factor for HCC.Although cirrhotic patients were excluded during enrollment and fibrosis 4 (FIB-4) index was adjusted in multivariate analysis, the disease severity of the enrolled patients in this study may still be heterogeneous, ranging from minimal to advanced liver damage.Without fully balancing the severity of liver damage, the inverse relationship between baseline HBV DNA level and on-treatment HCC risk might be an illusion.Last but not least, the authors proposed that antiviral treatment can be initiated early in patients with high viral load regard-less of ALT level for the prevention of HCC.However, there was no solid evidence to show the benefit of antiviral treatment in immune-tolerant patients.On the contrary, poor response to current treatments in those patients has been reported (5).Expanding current treatment indication without solid evidence would bring unnecessary potential side effects and the financial burden of long-term treatment for some patients.
Neuroprotection against ischemic stroke requires a specific class of early responder T cells in mice
Authors: Wei Cai, Ligen Shi, Jingyan Zhao, Fei Xu, Connor Dufort, Qing Ye, Tuo Yang, Xuejiao Dai, Junxuan Lyu, Chenghao Jin, Hongjian Pu, Fang Yu, Sulaiman Hassan, Zeyu Sun, Wenting Zhang, T. Kevin Hitchens, Yejie Shi, Angus W. Thomson, Rehana K. Leak, Xiaoming Hu, Jun Chen
Journal: Journal of Clinical Investigation (2022)

Immunomodulation holds therapeutic promise against brain injuries, but leveraging this approach requires a precise understanding of mechanisms. We report that CD8+CD122+CD49dlo T regulatory-like cells (CD8+ TRLs) are among the earliest lymphocytes to infiltrate mouse brains after ischemic stroke and temper inflammation; they also confer neuroprotection. TRL depletion worsened stroke outcomes, an effect reversed by CD8+ TRL reconstitution. The CXCR3/CXCL10 axis served as the brain-homing mechanism for CD8+ TRLs. Upon brain entry, CD8+ TRLs were reprogrammed to upregulate leukemia inhibitory factor (LIF) receptor, epidermal growth factor-like transforming growth factor (ETGF), and interleukin 10 (IL-10). LIF/LIF receptor interactions induced ETGF and IL-10 production in CD8+ TRLs. While IL-10 induction was important for the antiinflammatory effects of CD8+ TRLs, ETGF provided direct neuroprotection. Poststroke intravenous transfer of CD8+ TRLs reduced infarction, promoting long-term neurological recovery in young males or aged mice of both sexes. Thus, these unique CD8+ TRLs serve as early responders to rally defenses against stroke, offering fresh perspectives for clinical translation.
Breast Cancer Risk After Recent Childbirth
Authors: Hazel B. Nichols, Minouk J. Schoemaker, Jianwen Cai, Jiawei Xu, Lauren B. Wright, Mark N. Brook, Michael E. Jones, Hans-Olov Adami, Laura Baglietto, Kimberly A. Bertrand, William J. Blot, Marie-Christine Boutron-Ruault, Miren Dorronsoro, Laure Dossus, A. Heather Eliassen, Graham G. Giles, Inger T. Gram, Susan E. Hankinson, Judy Hoffman-Bolton, Rudolf Kaaks, Timothy J. Key, Cari M. Kitahara, Susanna C. Larsson, Martha Linet, Melissa A. Merritt, Roger L. Milne, Valeria Pala, Julie R. Palmer, Petra H. Peeters, Elio Riboli, Malin Sund, Rulla M. Tamimi, Anne Tjønneland, Antonia Trichopoulou, Giske Ursin, Lars Vatten, Kala Visvanathan, Elisabete Weiderpass, Alicja Wolk, Wei Zheng, Clarice R. Weinberg, Anthony J. Swerdlow, Dale P. Sandler
Journal: Annals of Internal Medicine (2018)

Parity is widely recognized as protective for breast cancer, but breast cancer risk may be increased shortly after childbirth. Whether this risk varies with breastfeeding, family history of breast cancer, or specific tumor subtype has rarely been evaluated.
Long-term wellbeing and neurocognitive functioning of diffuse low-grade glioma patients and their caregivers: A longitudinal study spanning two decades
Authors: Florien W Boele, Patricia W M den Otter, Jaap C Reijneveld, Philip C de Witt Hamer, Hinke F van Thuijl, Linda M C Lorenz, Pieter Wesseling, Frank J Lagerwaard, Martin J B Taphoorn, Mathilde C M Kouwenhoven, Tom J Snijders, Linda Douw, Martin Klein
Journal: Neuro-Oncology (2022)

While patients with diffuse low-grade glioma (LGG) often survive for years, there is a risk of tumor progression which may impact patients' long-term health-related quality of life (HRQOL) and neurocognitive functioning (NCF). We present a follow-up of LGG patients and their informal caregivers (T3) who took part in our previous HRQOL investigations (T1, M = 7 and T2 M = 13 years after diagnosis).Participants completed HRQOL (short form-36 health survey [SF-36]; EORTC-BN20), fatigue (Checklist Individual Strength [CIS]), and depression (Center for Epidemiological Studies-Depression [CES-D]) questionnaires and underwent NCF assessments. T3 scores were compared with matched controls. Changes over time (T1-T2-T3) on group and participant level were assessed. Where available, histology of the initial tumor was revised and immunohistochemical staining for IDH1 R132H mutant protein was performed.Thirty patients and nineteen caregivers participated. Of N = 11 with tissue available, 3 patients had confirmed diffuse LGG. At T3, patients (M = 26 years after diagnosis) had HRQOL and NCF similar to, or better than controls, yet 23.3% and 53.3% scored above the cut-off for depression (≥16 CES-D) and fatigue (≥35 CIS), respectively. Caregivers' HRQOL was similar to controls but reported high rates of fatigue (63.2%). Over time, patients' mental health improved (P < .05). Minimal detectable change in HRQOL over time was observed in individual patients (30% improvement; 23.3% decline; 20% both improvement and decline) with 23.3% remaining stable. NCF remained stable or improved in 82.8% of patients.While HRQOL and NCF do not appear greatly impacted during long-term survivorship in LGG, depressive symptoms and fatigue are persistent.
EANO - EURACAN - SNO Guidelines on circumscribed astrocytic gliomas, glioneuronal, and neuronal tumors
Authors: Roberta Rudà, David Capper, Adam D Waldman, Johan Pallud, Giuseppe Minniti, Thomas J Kaley, Eric Bouffet, Ghazaleh Tabatabai, Eleonora Aronica, Asgeir S Jakola, Stefan M Pfister, David Schiff, Andrew B Lassman, David A Solomon, Riccardo Soffietti, Michael Weller, Matthias Preusser, Ahmed Idbaih, Patrick Y Wen, Martin J van den Bent
Journal: Neuro-Oncology (2022)

In the new WHO 2021 Classification of CNS Tumors the chapter "Circumscribed astrocytic gliomas, glioneuronal and neuronal tumors" encompasses several different rare tumor entities, which occur more frequently in children, adolescents, and young adults. The Task Force has reviewed the evidence of diagnostic and therapeutic interventions, which is low particularly for adult patients, and draw recommendations accordingly. Tumor diagnosis, based on WHO 2021, is primarily performed using conventional histological techniques; however, a molecular workup is important for differential diagnosis, in particular, DNA methylation profiling for the definitive classification of histologically unresolved cases. Molecular factors are increasing of prognostic and predictive importance. MRI finding are non-specific, but for some tumors are characteristic and suggestive. Gross total resection, when feasible, is the most important treatment in terms of prolonging survival and achieving long-term seizure control. Conformal radiotherapy should be considered in grade 3 and incompletely resected grade 2 tumors. In recurrent tumors reoperation and radiotherapy, including stereotactic radiotherapy, can be useful. Targeted therapies may be used in selected patients: BRAF and MEK inhibitors in pilocytic astrocytomas, pleomorphic xanthoastrocytomas, and gangliogliomas when BRAF altered, and mTOR inhibitor everolimus in subependymal giant cells astrocytomas. Sequencing to identify molecular targets is advocated for diagnostic clarification and to direct potential targeted therapies.
Endoscopy International Open – recently published
Journal: Endoscopy (2018)

Comment on: Clinical outcomes of the “resect and discard” strategy using magnifying narrow-band imaging for small (< 10 mm) colorectal polypsEndosc Int Open 2018; 06(12): E1382-E1389DOI: 10.1055/a-0650-4362 Comment on: Endoscopic ultrasound-guided choledochoduodenostomy with a lumen-apposing metal stent through an uncovered metal duodenal stentEndosc Int Open 2018; 06(12): E1395-E1397DOI: 10.1055/a-0735-9254 Comment on: Comparison of early and delayed EUS-guided drainage of pancreatic fluid collectionEndosc Int Open 2018; 06(12): E1398-E1405DOI: 10.1055/a-0751-2698
Highlights of This Issue
Journal: Clinical Cancer Research (2018)

Raja and colleagues explored changes in levels of ctDNA in advanced/metastatic NSCLC and UC patients receiving the anti-PD-L1 monoclonal antibody durvalumab. Reduction in ctDNA levels at 6 weeks was associated with RECIST responses, PFS and OS, and often preceded RECIST response. Thus, early changes in ctDNA may predict long-term benefit from immunotherapy and enable treatment decisions, particularly in indications in which assessing radiographic responses may be difficult.Mesothelioma is an aggressive cancer with limited treatment options and often with resistance to immunotherapy. To overcome resistance to previous treatments, Tallón de Lara and colleagues showed that the synergy of gemcitabine and immune checkpoint inhibitors (ICI) outperformed single treatment in a preclinical mouse model of mesothelioma. Two patients with mesothelioma, who did not respond to the single treatments, responded to the combination when given. Interestingly, dexamethasone, widely used in the clinics to treat side effects, dampened the response in the preclinical model. This study gives a new rationale to combine ICI and gemcitabine in mesothelioma patientsPatients with leukemia can develop bone defects (osteonecrosis) in hip bones, which can lead to joint collapse. A new treatment involves drilling a track in the affected bone (decompression surgery), aspirating marrow cells from the pelvis and implanting them into the bone defect. To visualize the cells, the authors treated patients with an iron supplement 1 to 2 days before the surgery. The cells in the bone marrow took up the iron. When iron-loaded cells were then harvested from the bone marrow and transplanted in the bone defect, they could be detect with MR imaging. This new stem cell imaging approach may help to better understand and optimize stem cell therapies.TRC105 is a neutralizing antibody targeting the TGF-β coreceptor endoglin and is currently being tested in clinical trials as antiangiogenic therapy. TRC105 prevents binding of BMP-9 to endoglin, which controls (tumor) angiogenesis. Paauwe and colleagues show that endoglin also is expressed on cancer-associated fibroblasts (CAFs) and reveal a role for this receptor in CAF invasion. TRC105 treatment reduced invasive capacity of CAFs in vitro and metastatic spread of CRC in vivo. This underlines the potential of TRC105 to be more than a “classic anti-angiogenic drug,” targeting both endothelium and CAF, thereby limiting metastatic spread on multiple levels.
Targeted inhibition of osteoclastogenesis reveals the pathogenesis and therapeutics of bone loss under sympathetic neurostress
Authors: Bingdong Sui, Jin Liu, Chenxi Zheng, Lei Dang, Ji Chen, Yuan Cao, Kaichao Zhang, Lu Liu, Minyan Dang, Liqiang Zhang, Nan Chen, Tao He, Kun Xuan, Fang Jin, Ge Zhang, Yan Jin, Chenghu Hu
Journal: International Journal of Oral Science (2022)

Abstract Sympathetic cues via the adrenergic signaling critically regulate bone homeostasis and contribute to neurostress-induced bone loss, but the mechanisms and therapeutics remain incompletely elucidated. Here, we reveal an osteoclastogenesis-centered functionally important osteopenic pathogenesis under sympatho-adrenergic activation with characterized microRNA response and efficient therapeutics. We discovered that osteoclastic miR-21 was tightly regulated by sympatho-adrenergic cues downstream the β2-adrenergic receptor (β 2 AR) signaling, critically modulated osteoclastogenesis in vivo by inhibiting programmed cell death 4 (Pdcd4), and mediated detrimental effects of both isoproterenol (ISO) and chronic variable stress (CVS) on bone. Intriguingly, without affecting osteoblastic bone formation, bone protection against ISO and CVS was sufficiently achieved by a (D-Asp 8 )-lipid nanoparticle-mediated targeted inhibition of osteoclastic miR-21 or by clinically relevant drugs to suppress osteoclastogenesis. Collectively, these results unravel a previously underdetermined molecular and functional paradigm that osteoclastogenesis crucially contributes to sympatho-adrenergic regulation of bone and establish multiple targeted therapeutic strategies to counteract osteopenias under stresses.
Comparison of different field tests to assess the physical capacity of post-COVID-19 patients
Authors: R. Peroy-Badal, A. Sevillano-Castaño, R. Torres-Castro, P. García-Fernández, J.L. Maté-Muñoz, C. Dumitrana, E. Sánchez Rodriguez, M.J. de Frutos Lobo, J. Vilaró
Journal: Pulmonology (2022)

In coronavirus disease (COVID-19), physical capacity is one of the most impaired sequelae. Due to their simplicity and low cost, field tests such as the six-minute walk test (6MWT) are widely used However, in many places it is difficult to perform them and alternatives can be used such as the 1 min sit-to-stand test (1min-STST) or the Chester step test (CST). Therefore, our objective was to compare the 6MWT, 1min-STST and the CST in post-COVID-19 patients.
Molecular profiling and precision medicine in rare gastrointestinal cancers within EURACAN in the SPECTA Arcagen study (EORTC-1843): too few patients with matched treatment in Europe
Authors: A Lamarca, M Morfouace, S Tejpar, J Oliveira, A Capela, N Penel, C Gennigens, B Brasiuniene, J Peron, A Stevovic, J-Y Blay, H-J Klümpen
Journal: Annals of Oncology (2022)
Invariant natural killer T cells minimally influence gut microbiota composition in mice
Authors: Qiaochu Lin, Meggie Kuypers, Zhewei Liu, Julia K Copeland, Donny Chan, Susan J Robertson, Jean Kontogiannis, David S Guttman, E. Kate Banks, Dana J Philpott, Thierry Mallevaey
Journal: Gut Microbes (2022)

Invariant Natural Killer T (iNKT) cells are unconventional T cells that respond to glycolipid antigens found in microbes in a CD1d-dependent manner. iNKT cells exert innate-like functions and produce copious amounts of cytokines, chemokines and cytotoxic molecules within only minutes of activation. As such, iNKT cells can fuel or dampen inflammation in a context-dependent manner. In addition, iNKT cells provide potent immunity against bacteria, viruses, parasites and fungi. Although microbiota-iNKT cell interactions are not well-characterized, mounting evidence suggests that microbiota colonization early in life impacts iNKT cell homeostasis and functions in disease. In this study, we showed that CD1d−/− and Vα14 Tg mice, which lack and have increased numbers of iNKT cells, respectively, had no significant alterations in gut microbiota composition compared to their littermate controls. Furthermore, specific iNKT cell activation by glycolipid antigens only resulted in a transient and minimal shift in microbiota composition when compared to the natural drift found in our colony. Our findings demonstrate that iNKT cells have little to no influence in regulating commensal bacteria at steady state.Abbreviations: iNKT: invariant Natural Killer T cell; αGC: α-galactosylceramide
Clinical Images: Nivolumab‐induced tracheobronchial chondritis in a patient with hypopharyngeal cancer
Authors: Kazu Hamada‐Ode, Yoshinori Taniguchi, Marina Osaki, Rika Yoshimatsu, Noriko Nitta
Journal: Arthritis & Rheumatology (2022)

Disclosure Form Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
Nuclear Receptor Subfamily <scp>4A</scp> Signaling as a Key Disease Pathway of <scp>CD1c</scp>+ Dendritic Cell Dysregulation in Systemic Sclerosis
Authors: Nila H. Servaas, Sanne Hiddingh, Eleni Chouri, Catharina G. K. Wichers, Alsya J. Affandi, Andrea Ottria, Cornelis P. J. Bekker, Marta Cossu, Sandra C. Silva‐Cardoso, Maarten van der Kroef, Anneline C. Hinrichs, Tiago Carvalheiro, Nadia Vazirpanah, Lorenzo Beretta, Marzia Rossato, Femke Bonte‐Mineur, Timothy R. D. J. Radstake, Jonas J. W. Kuiper, Marianne Boes, Aridaman Pandit
Journal: Arthritis & Rheumatology (2022)

This study was undertaken to identify key disease pathways driving conventional dendritic cell (cDC) alterations in systemic sclerosis (SSc).Transcriptomic profiling was performed on peripheral blood CD1c+ cDCs (cDC2s) isolated from 12 healthy donors and 48 patients with SSc, including all major disease subtypes. We performed differential expression analysis for the different SSc subtypes and healthy donors to uncover genes dysregulated in SSc. To identify biologically relevant pathways, we built a gene coexpression network using weighted gene correlation network analysis. We validated the role of key transcriptional regulators using chromatin immunoprecipitation (ChIP) sequencing and in vitro functional assays.We identified 17 modules of coexpressed genes in cDCs that correlated with SSc subtypes and key clinical traits, including autoantibodies, skin score, and occurrence of interstitial lung disease. A module of immunoregulatory genes was markedly down-regulated in patients with the diffuse SSc subtype characterized by severe fibrosis. Transcriptional regulatory network analysis performed on this module predicted nuclear receptor 4A (NR4A) subfamily genes (NR4A1, NR4A2, NR4A3) as the key transcriptional regulators of inflammation. Indeed, ChIP-sequencing analysis indicated that these NR4A members target numerous differentially expressed genes in SSc cDC2s. Inclusion of NR4A receptor agonists in culture-based experiments provided functional proof that dysregulation of NR4As affects cytokine production by cDC2s and modulates downstream T cell activation.NR4A1, NR4A2, and NR4A3 are important regulators of immunosuppressive and fibrosis-associated pathways in SSc cDCs. Thus, the NR4A family represents novel potential targets to restore cDC homeostasis in SSc.